Human infection with species of the Leishmania genus causes a wide range of disease manifestations ranging from asymptomatic infection to clinical leishmaniasis, which can be severe and even fatal. In Brazil, Leishmania braziliensis is the most frequent species causing cutaneous leishmaniasis and its more severe form mucosal leishmaniasis, whereas Leishmania chagasi is responsible for visceral leishmaniasis. The outcome of either L. braziliensis and L. chagasi infections can include self-resolution, or they can evolve into clinically apparent and severe disease. Mucosal leishmaniasis patients have a biased immune response to parasite antigens manifested by high TNF-oc and IFN-y but low IL-10 production, and decreased responsiveness to suppression by IL-10 and TGF-p. In contrast, VL patients present with high levels of IL-10 and TNF-a and low levels of INF-y The major goals of this project are to identify genes involved in susceptibility/resistance to distinct clinical forms of leishmaniasis. The specific aims of this project are: (1) To strengthen linkage findings of VL population. New multiplex will be used for fine mapping studies to localize the genes, supplemented by family based association analysis that incorporates information from simplex families. (2) To expand candidate genes and their role in determining risk of ML among families ascertained through cutaneous or mucosal leishmaniasis cases (3.) To examine autosomal SNP markers genotyped for this project in addition to markers on the Y chromosome and mitochondrial DNA in families with mucosal, cutaneous and visceral leishmaniasis to assess the extent of genetic admixture in these populations. We will incorporate this admixture information into the analytical strategy. Since the general Brazilian population is a mixture of three major racial groups (European, African and Amerindian), formal admixture analysis should provide a better test for genes controlling risk to different clinical outcomes of Leishmania infection. We hope at the end of the study to have a better understanding of innate human immune factors involved in determining the severity of disease due to the Leishmania species. Such knowledge may reveal arms of the immune system that are important for cure.